Screening of natural products for therapeutic activity against solid tumors (original) (raw)
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Clinical development of anticancer agents from natural products
Stem Cells, 1994
Recent years have seen the introduction into clinical trials of new classes of chemotherapeutic agents which a r e derived from natural sources and have novel mechanisms of action. Examples of some of these newer classes of agents are presented here to illustrate both the opportunities they represent with respect to cancer treatment applications and the challenges which they represent from the clinical development perspective. Cumulatively the problems encountered with the development of the agents described are representative of the spectrum of issues encountered in the development of natural products, ranging from initial characterization and purification through the difficulties encountered in obtaining sufficient quantities of material for preclinical studies and then ultimately for clinical trials. Since these agents have unique mechanisms of action and are often exquisitely dose-and schedule-dependent in preclinical studies, they represent significant complexities with respect to determining the optimal regimen of administration clinically. The particular agents chosen for description here represent the spectrum of natural sourcederived materials as well as mechanisms of action. The taxanes are derived from tree sources and interfere with the mitotic spindle apparatus; the camptothecins, while also derived from trees, appear to exert their activity through interactions with topoisomerase I. Bryostatin, derived from a marine animal, has powerful effects on protein kinase C (PKC), and therefore affects signal transduction pathways within cells.
In-Vitro Screening of Some Plant Extracts for Their Potential Anticancer Activity
African Journal of Traditional, Complementary and Alternative Medicines
Background: Natural products have been shown to be reliable sources of anticancer medicines although there is still a consistent demand for new therapeutic natural products for cancer treatment with minimal side-effects. Materials and Methods: In this study, six plant extracts (Grevillea robusta; Euphorbia millii; Euphorbia royleana; Aloe grandidentata; Bauhinia corniculate; and Cassia fistula) were screened for the presence of phytochemical metabolites as saponins, tannins, cardiac glycosides, alkaloids, flavonoids, anthraquinones and sterols, using qualitative tests. Antiproliferative screening assay was performed on a panel of three cancer cell-lines (HepG-2, HCT-116 and MCF-7) using MTT assay, and cytotoxicity was determined using WI-38 human fibroblast cell-line. Results: Some plant extracts reduced cellular growth for the selected cancerous cell-lines. For example, E. royleana and A. grandidentata extracts reduced HepG-2 cellular growth with IC50 of 0.42 and 0.53µg/mL, respectively. Moreover, A. grandidentata and C. fistula reduced cellular growth of MCF-7 with IC50 of 0.37 and 0.67 µg/mL, respectively. Conclusion: E. royleana, A. grandidentata and C. fistula showed significant anti-proliferative activity against HepG-2 and MCF-7 cell-lines with non-cytotoxic nature. This suggests their potential role as anticancer agents against these types of cancer. The presence of flavonoids, sterols and anthraquinones may suggest their enhanced anti-proliferative activities. Therefore, this study has shed light on the possible use of these extracts as potential sources of natural products-based therapy for cancer.
A new paradigm for the development of anticancer agents from natural products
Journal of experimental therapeutics & oncology, 2006
A novel pharmacology paradigm has been developed which quickly and efficiently moves prospective anticancer drugs from the discovery phase through pharmacology testing and into therapeutic trial assessment. Following discovery, the drug is first assessed in a clonogenic assay which determines the cytotoxic effect of different concentrations of the drug at 3 different exposure durations: 2h, 24h and continuous (168 h). Second, pharmacokinetic information is obtained in both plasma and tumor for the drug administered at the maximum tolerated dose given intravenously. The first study defines the time-concentration profile required to obtain a specific cell survival for the tumor cells; the second study determines the concentration-time profile that can be obtained in both plasma and tumor at the maximum tolerated dose of the drug. The integration of this information determines whether a successful therapeutic trial is possible. Only when a drug shows therapeutic efficacy is a proteomic...
TJPRC, 2013
Cancer is a complex disease which is associated with cell signaling, DNA damage and cell cycle. Cancer is a multifactorial in origin .Cancer causes for 12.5% of deaths worldwide. Cancer treatment methods in cancer therapy like radiation and chemotherapy and using synthetic drugs leading to side effects. Therefore, there is a lot of demand to identify and develop effective novel therapeutic agents to treat many diseases. Plants are richest and unique source of energy, oxygen, metabolites and therapeutic agents. Many compounds of plant derivatives are very active against many dreadful diseases including cancer. Humans benefit from using many of the plants as medicinal purposes to combat diseases and microbes. Since plants are the natural, safe and best source in providing these active components especially anticancer drugs. Hence it is very essential to study about natural products and their potential role in therapeutic use. This review paper focuses mainly on achievements in cancer therapy using plant products and the potential clinical applications of medicinal plants and the role of their products, especially as anticancer drugs.
In vitro screening of tumoricidal properties of international medicinal herbs: part II
Phytotherapy Research, 2010
With growing use of anticancer complementary and alternative medicines (CAMs) worldwide, there is a need to assess and screen commercially available natural products for relative tumoricidal properties under standard experimental conditions. In the current study, we screened and ranked 264 traditional Chinese and Egyptian herbal medicines for tumoricidal potency against malignant neuroblastoma in vitro. The data obtained show that tumoricidal potencies of plants were randomly dispersed throughout similar orders, families and genera under the Division: Magnoliophyta, class: Magnoliopsida, subclasses: Asteridae, Caryophyllidae, Dilleniidae, Hamamelididae, Magnoliidae and Rosidae. The most potent plant extracts (LC 50 < 0.08 mg/ml) were prepared from gromwell root also known as 'Hong Tiao Zi Cao' (Lithospermum Erythrorhizon) Family (Boraginaceae) > beth root (Trillium Pendulum), Family (Liliaceae) and galbanum (Ferula Galbaniflua), Family (Apiaceae). Gromwell root is traditionally used in the preparation of Chinese medicinal tea. In addition, galbanum was highly regarded for its sacred and medicinal value according to ancient texts and the bible. Future research will be required to isolate and identify chemical constituents within these plants which are responsible for tumoricidal effects.
Chemistry & Biodiversity, 2006
In an attempt to determine the relationships between the plant profiles (country of collection, taxonomy, plant part) and the compound classes isolated with cytotoxic activity against a panel of human tumor cell lines, the data compiled from a 15-year anticancer drug-discovery project were subjected to an analysis of variance (ANOVA). The results indicate significant trends in cytotoxic activity relative to collection location, taxonomy, plant part, and compound classes isolated. Plant collections were made in tropical forests in six countries, with collections from Ecuador resulting in higher activity than those from Indonesia and Peru. Interestingly, collections from Florida were not statistically different than those from the countries with higher biodiversity. One hundred and forty-five families were represented in the collections, with the Clusiaceae, Elaeocarpaceae, Meliaceae, and Rubiaceae having low ED 50 (half maximal effective dose) values. Especially active genera included Aglaia, Casearia, Exostema, Mallotus, and Trichosanthes. Roots and below-ground plant materials were significantly more active than aboveground materials. Cucurbitacins, flavaglines, anthraquinones, fatty acids, tropane alkaloids, lignans, and sesquiterpenoids were significantly more active than xanthones and oligorhamnosides. The results from this study should serve as a guide for future plant collection endeavors for anticancer drug discovery. isolation [2] [4], and the elimination or scaling down of natural-product research programs at pharmaceutical companies and governmental agencies [1] [3]. A majority of new medicines derived from plant secondary metabolites have been applied toward the treatment and/or prevention of cancer [2] [5]. Since 1990, there has been a 22% increase in cancer incidence and mortality, with over 10 million new cases and over 6 million deaths worldwide in 2000 (all tissues excluding non-melanoma skin) [8]. Progress has been made in cancer chemotherapy, a considerable portion of which can be attributed to plant-derived drugs [5]. Anticancer agents from plants currently in clinical use comprise four main compound classes (including their synthetic and/or semi-synthetic derivatives): Vinca (or Catharanthus) alkaloids from Catharanthus roseus (L.) G. Don (Apocynaceae; formerly Vinca rosea L.) [9] [10], epipodophyllotoxins from Podophyllum peltatum L. (Berberidaceae) [11], taxanes from Taxus brevifolia Nutt. (Taxaceae) [12-14], and camptothecins from Camptotheca acuminata Decne. (Nyssaceae) [12] [15]. Taxane and camptothecin analogues accounted for estimated sales of over 2.75 billion dollars in 2002, or approximately one third of the global market [13]. Two other compound classes from plants are showing promising results in advanced clinical trials, namely, the combretastatins and their derivatives from Combretum caffrum Kuntze (Combretaceae) [16] [17] and the homoharringtonine alkaloids from Cephalotaxus harringtonia C. Koch (Cephalotaxaceae) [18]. Despite considerable advances in cancer treatment, new drugs are still needed, since some cancers have become resistant to currently available treatments and certain types of cancer lack appropriate drug treatments. As part of a multidisciplinary, multi-institutional research project entitled Novel Strategies for the Discovery of Plant-Derived Anticancer Agents, funded through the National Cooperative Drug Discovery Group (NCDDG) from the U.S. National Cancer Institute (NCI), we have been investigating the anticancer activity of higher plant species since 1990 (see the most recent review [19]). The project has involved plant collection, extract preparation, screening of extracts in cytotoxicity and mechanism-based in vitro bioassays, dereplication of active plant species, activityguided fractionation, compound isolation and structure elucidation, in vivo testing in hollow-fiber and xenograft mouse models, lead optimization, and compound development. Although extensive data have been collected throughout the course of this project, this paper represents the first in-depth statistical analysis concerning the relationship between the plant samples collected, the compound classes isolated, and the resultant in vitro biological test data obtained. This study examines the statistical relationships between the plant profiles, including country of collection, taxonomy, and plant part, of the samples collected through our NCDDG project over a ten-year period (1995-2005) and their cytotoxicity expressed as ED 50 (half-maximal effective dose) values in a panel of human cancer cell lines. Statistical analyses of such a data set may provide insight into taxonomic and ecological patterns of the plants collected related to biological activity, and as such, may help guide future plant-collection efforts in a drug-discovery endeavor. This study also examines the statistical relationship between compound classes isolated from plants during the entire project period (1990-2005) and their cytotoxicity in a panel of human cancer cell lines. Those compound classes found to be most active can be considered during dereplication processes in future drug-discovery efforts from plants. Informa
Discovery and development of anticancer agents from plants
Journal of Experimental Therapeutics and Oncology, 2002
A novel in vitro assay for the discovery of anticancer agents was used to examine aqueous and organic extracts from 1847 plants collected mainly in the U.S. Southwest and West. The assay results were separated into 5 categories: inactive (62%), equally active (36%), equally active and potent (0.5%), solid tumor selective (1.4%), and human selective (0.8%). Extracts from the latter three categories were fractionated using the in vitro assay to biodirect each step. Psorothamnus emoryi extracts were solid tumor selective and yielded two active compounds upon fractionation: dalrubone and 5-methoxydalrubone. Calocedrus decurrens was equally active and potent and yielded deoxypodophyllotoxin as the active compound. Linanthus floribundus was human selective and yielded strophanthidin as the active compound. The potential of this assay to discover novel anticancer agents from the active extracts is discussed.
Novel Strategies for the Discovery of Plant-Derived Anticancer Agents
Pharmaceutical Biology, 2003
Work has continued on the investigation of plants, collected mainly from tropical rainforests, as potential sources of new cancer chemotherapeutic agents. About 400 primary samples are obtained each year, with the chloroform-soluble extract of each being screened against a battery of in vitro assays housed at the three consortial sites in our current National Cooperative Drug Discovery Group (NCDDG) research project. An HPLC-MS dereplication procedure designed to screen out "nuisance" compounds has been refined. Several hundred secondary metabolites that are active in one or more of the primary assays utilized have been obtained in the project to date, and are representative of wide chemical diversity. Some of these are also active in various in vivo assays, inclusive of the hollow fiber assay, which was installed recently as part of our collaborative research effort. A number of bioactive compounds of interest to the project are described.
Natural Products/Bioactive Compounds as a Source of Anticancer Drugs
Cancers
Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer agents to overcome its mortality rate. The discovery of novel and effective anticancer agents from natural sources has been the main point of interest in pharmaceutical research because of attractive natural therapeutic agents with an immense chemical diversity in species of animals, plants, and microorganisms. More than 60% of contemporary anticancer drugs, in one form or another, have originated from natural sources. Plants and microbial species are chosen based on their composition, ecology, phytochemical, and ethnopharmacological properties. Plants and their derivatives have played a significant role in producing effective anticancer agents. Some plant derivatives include vincristine, vinblastine, irinotecan, topotecan, etoposide, podophyllotoxin, and paclitaxel. Based on their particular activity, a number of o...